ideasIdea
Test alternating drug schedules against giving both drugs at once
Two drugs might work better given in turns rather than together, with less toxicity. Almost no trial has tested this.
Evolutionary models and mouse studies suggest that alternating two non-cross-resistant agents can delay resistance as well as concurrent dosing at lower cumulative toxicity, and that some pairs are antagonistic when concurrent (for example cytostatic agents that protect cells from cytotoxics). Randomised trials of schedule rather than of drug are rare.
Hypothesis
For at least one common doublet (for example an EGFR TKI plus chemotherapy in EGFR-mutant lung cancer), an alternating schedule achieves non-inferior progression-free survival with at least 30% fewer grade 3 or worse adverse events than concurrent dosing.
Rationale
FLAURA2 showed concurrent osimertinib plus chemotherapy improves progression-free survival but with substantial added toxicity. Cell-cycle arguments predict that sequence within a cycle matters.
What would test it
A randomised phase 2 of concurrent versus alternating osimertinib and platinum-pemetrexed with progression-free survival and toxicity endpoints, plus ctDNA kinetics to compare resistance emergence.
Maturity
preclinical evidence
Who has to act
research
Cost to try
Medium ($1M to $50M)
Years to first evidence
4
Bottlenecks it attacks
- Too many combinations to test · There are thousands of possible drug pairs and sequences. Trials can test a few dozen a year.
- Acquired resistance to every therapy · Nearly every targeted therapy stops working within months to a few years as the tumour adapts.